None.
Not Applicable.
(1) Field of the Invention
The present invention relates to a process for the direct synthesis of polymers from dimeric cyclic esters. In particular, the present invention relates to polylactic acid (PLA or polylactide) from racemic lactide or a polymandelide from mandelide. The process particularly relates to a racemic metal organic ligand catalyst such as racemic salbinap that catalyzes the polymerization of racemic dimeric cyclic ester monomers such as poly(L-lactide) and poly(D-lactide) to a polylactide stereocomplex.
(2) Description of Related Art
Poly(hydroxybutyrate) and poly(lactide) herein xe2x80x9cpolylactidexe2x80x9d (Chiellini et al., Adv. Maters. 8: 305-313 (1996)) are among the most widely studied degradable polymer systems, and polylactide is now being commercialized as a commodity polymer for high volume commercial applications such as fibers and packaging materials (Thayer, Chem Eng. News 75: 14-16 (1997)). Polylactic acid (PLA) is an attractive polymer because it can be derived from renewable resources and provides a biodegradable alternative to polymers obtained from petrochemical sources (Sinclair, Macromol. Sci.-Pure Appl. Chem. A33: 585-597 (1996)). PLA is prepared by the ring opening polymerization (ROP) of lactide, the cyclic dimer of lactic acid. Currently, enantiopure L-lactide is required for preparing crystalline materials. Therefore, considerable effort has been expended in preparing L-lactide via fermentation routes. To date there have not been reported any examples where crystalline PLA has been prepared from a racemic mixture of D- and L-lactide using an achiral catalyst.
Commercial polylactides usually are synthesized from lactide monomers prepared from a single lactic acid enantiomer, and because the resulting polymers are stereoregular, they have high degrees of crystallinity (Huang et al., Macromols. 31: 2593-2599 (1998)). The mechanical properties of crystalline polymers are stable to near the polymer melting point, and thus they have higher use temperatures than their amorphous analogs. For example, polymerization of L-lactide gives a semicrystalline polymer with a melting transition near 180xc2x0 C. and glass transition (Tg) of about 67xc2x0 C. (Zhang et al., Macromol. Sci.-Rev. Macromol. Chem. Phys. C33: 81-102 (1993)), properties that make it useful for applications ranging from degradable packaging to surgical implants and matrices for drug delivery (Hollinger, Biochemical Applications of Synthetic Degradable Polymers; CRC Press: Boca Raton, Fla., 1995).
In contrast, the polymer derived from rac-lactide, a 1:1 mixture of D and L-lactide, yields amorphous polymers with glass transitions near room temperature. Although L-lactide can be prepared with relatively high enantiopurity from corn fermentation, the requirement for an enantiopure monomer places restrictions on the polymer synthesis.
Chiral catalysts have been employed to effect kinetic resolution of racemic lactide. For example, Spassky et al. (Macromol. Chem. Phys. 197: 2627-2637 (1996)) reported kinetic resolutions of rac-lactide by employing a chiral Schiff""s base complex of aluminum, (xe2x88x92)-1. FIG. 1A shows a scheme for the polymerization of L-lactide and D-lactide to isotactic-L-PLA by catalyst (xe2x88x92)-1. The structure for catalyst (xe2x88x92)-1 is shown in FIG. 2 wherein R is a methyl group. At low conversions, high enantiomeric enrichment in the polymer was observed. In the kinetic resolution of rac-lactide by catalyst (xe2x88x92)-1, the enantiomeric excess at 20% conversion was 88% (Spassky et al., Macromol. Chem. Phys. 197: 2627-2637 (1996)). This indicated that the catalyst can override the tendency for syndiotactic placements that are typically favored by chain-end control (Thakur et al., Macromols. 31: 1487-1494 (1998)). At higher conversions, the enantiomeric enrichment in the polymer decreased. The drop in selectivity can be attributed to the fact that the relative concentration of the xe2x80x9cwrongxe2x80x9d isomer increases in the monomer pool as the desired enantiomer is incorporated in the polylactide.
In a recent report, Coates et al. effected the syndiotactic polymerization of meso-lactide by using the isopropoxide catalyst (xe2x88x92)-2 (Ovitt et al., J. Am. Chem. Soc. 121: 4072-4073 (1999)). The scheme for this reaction is shown in FIG. 1B. The structure for catalyst (xe2x88x92)-2 is shown in FIG. 2 wherein iPr is isopropoxide. Since meso-lactide possesses two stereocenters of opposite configuration, the concentration of D and L stereocenters remained constant and the intrinsic selectivity of the catalyst was not diminished by statistical depletion of the preferred stereocenter.
An interesting effect of stereoregularity on lactide properties was first reported by Tsuji and co-workers (Ikada et al., Macromols. 1987, 20: 904-906; Tsuji et al., Macromols. 24: 2719-2724 (1991); Brizzolara et al., Macromols. 29: 191-197 (1996)). As shown in FIG. 1C, upon mixing, L-PLA and D-PLA form a stereocomplex that has a Tm 230xc2x0 C., which is 50xc2x0 C. higher than the Tm for either of the homochiral D- or L-PLA polymers. Preparation of this stereocomplex presently requires parallel ROP of D- and L-lactide with subsequent combination of the chiral polylactide chains. Despite the improved mechanical properties of the stereocomplex, practical applications of the stereocomplex have been prohibitive because of the requirement that separate pools of enantiopure lactide monomers must first be polymerized to enantiopure polymers before combining to make the stereocomplex.
Since lactic acid is commercially available in racemic form, it would be desirable that crystalline polymers similar in properties to the PLA stereocomplex made from enantiopure lactide monomers be prepared from a racemic mixture of lactides. This would provide a simple route to polylactide formation because it would eliminate the need for enantioselective fermentation routes for the synthesis of polylactide monomers.
While a broad range of physical properties is available from polymers consisting of Poly(hydroxybutyrate)s and poly(lactide), one unmet need is a glassy, degradable polymer with a high glass transition temperature (T). The backbone of polylactide is relatively flexible resulting in a Tg near 60xc2x0 C., but substituting an aromatic ring for the methyl group of polylactide should, by analogy to polystyrene, result in a polymer with a significantly higher Tg. Thus, mandelide, the dimer of mandelic acid (2-hydroxy phenylacetic acid), is a particularly intriguing monomer for ring opening polymerization.
Prior art attempts at preparing polymandelides have produced polymers with number average molecular weights less than 5,000, too low for most practical applications. No glass transition temperatures were reported for these polymers. Direct condensation of 1-bromophenyl acetic acid in the presence of triethylamine (Pinkus et al., J. Polymer Sci. Part A-Polymer Chem. 27: 4291-4296 (1989)), transesterification of methyl mandelate (Domb, J. Polymer Sci. Part A-Polymer Chem. 31: 1973-1981 (1993)), and condensation of mandelic acid (Whitesell et al., Chem. Maters. 2: 248-254 (1990)) all provided low molecular weight polymers with degrees of polymerization near 30. Several indirect routes to polymandelide have also been reported. In the earliest synthesis of the homopolymer of mandelic acid, the trimethyltin ester of xcex1-bromophenyl acetic acid was pyrolyzed and the resulting viscous solid was identified as polymandelide (Okada et al., J. Organometal. Chem. 54: 149-152 (1973)). Deoxy-polymerization of phenylglyoxalic acid using cyclic phosphites yielded oligomers (Kobayashi et al., Polymer Bull. 3: 585-591 (1980)), and ring opening polymerization (with loss of CO2) of the anhydridocarboxylate of mandelic acid gave polymandelide with degrees of polymerization as high as 30(Smith et al., Macromol. Chem.-Phys. Makromol. Chem. 182: 313-324 (1981)). The latter method proceeds at room temperature and is claimed to proceed with retention of configuration, although crystalline polymers were not formed.
A series of articles reported the preparation and degradability of low molecular weight mandelic acid copolymers (Mn less than 2,000) by the direct condensation of L-lactic acid and D,L-mandelic acid (Imasaka et al., Macromol. Chem.-Phys. Makromol. Chem. 191: 2077-2082 (1990); Imasaka et al., Intl. J. Pharma. 81: 31-38 (1992); Fukuzaki et al., Euro. Polymer J. 26: 1273-1277 (1990); Fukuzaki et al., Macromol. Chem.-Phys. Makromol. Chem. 190: 2407-2415 (1989)). These copolymers covered the entire computational range from 0-100% mandelic acid and were evaluated as potential drug carriers. Lactic acid based poly(ester-urethane)s have been reported that contain up to 20 mole % D,L-mandelic acid in low molecular weight poly(lactic acid) segments (Kylma et al., J. Appl. Polymer Sci. 63: 1865-1872 (1997)). Increasing the mandelic acid content of these polymers led to an increase in the Tg of the lactide segment.
Therefore, there is a need for a process for preparing high molecular weight polymandelide, a polymer that would share many of the physical properties of polystyrene, but with the added feature of being biodegradable.
Patent references relevant to the present invention are U.S. Pat. No. 5,235,031 to Drysdale et al.; U.S. Pat. No. 5,225,129 to van den Berg; U.S. Pat. No. 5,076,983 to Loomis et al.; U.S. Pat. No. 5,053,522 to Muller; U.S. Pat. No. 5,053,485 to Nieuwenhuis et al.; U.S. Pat. No. 3,960,152 to Augurt et al.; U.S. Pat. No. 4,057,537 to Sinclair; U.S. Pat. No. 5,028,667 to McLain et al.; U.S. Pat. No. 5,359,027 to Perego et al.; U.S. Pat. No. 5,801,223 to Lipinsky et al.; U.S. Pat. No. 5,196,551 to Bhatia et al.; U.S. Pat. No. 5,274,127 to Sinclair et al.; U.S. Pat. No. 5,332,839 to Benecke et al.; and U.S. Pat. No. 5,319,107 to Benecke et al.
The present invention provides a process for the direct synthesis of high melting polymers made from dimeric cyclic esters. In particular, the present invention provides a process for synthesis of polylactic acid (PLA) from racemic materials such as racemic lactide and synthesis of polymandelides from mandelides. The process further provides racemic metal organic ligand catalysts such as racemic salbinap that catalyzes the polymerization of racemic dimeric cyclic ester monomers to a polylactide stereocomplex.
Thus, the present invention provides a process for the preparation of a crystalline polymer of a dimeric cyclic ester which comprises providing an anhydrous dimeric cyclic ester of the formula 
wherein R1 and R3 are selected from the group consisting of linear, branched and unsaturated alkyl containing 1 to 24 carbon atoms, aryl, and aromatic, and R2 and R4 are selected from the group consisting of hydrogen and methyl; mixing an anhydrous metal organic ligand catalyst with the anhydrous dimeric cyclic ester under anhydrous conditions to provide a reaction mixture; heating the reaction mixture to polymerize the dimeric cyclic ester to form the polymer in the reaction mixture (preferably the mixture is heated to a temperature between about 20xc2x0 C. and 200xc2x0 C.; and removing the polymer from the reaction mixture, wherein the steps (a) to (d) are conducted in the presence of less than 2 mole percent water based upon the ester.
In the process, the catalyst preferably comprises a racemic salbinap and the metal is selected from the group consisting of Y, Sc lanthanide elements, Group 14, transition elements, and Group 13 elements except thalium elements. In particular, it is preferable that the catalyst is rac-(salbinap)MOAlk wherein M is the metal and Alk is a lower alkyl containing 1 to 6 carbon atoms. Preferably, the catalyst is selected from the group consisting of rac-(salbinap)AlEt wherein Et is ethyl and rac-(salbinap)AlOiPr wherein iPr is isopropyl. In a preferred embodiment, the cyclic ester is an R,S cyclic ester. Further, the polymer produced by the above method has a Polymer Dispersity Index (PDI) of between about 1 and 2.0. Thus, the process produces a poly(dimeric cyclic ester) having a PDI of between about 1 and 2.0.
Further, the present invention provides a process for the preparation of a crystalline polylactic acid (PLA) which includes poly(L-lactide) and poly (D-lactide) polymer chains which comprises reacting a racemic mixture of a lactide with a metal organic ligand catalyst which is racemic so that the crystalline PLA is produced. Preferably, the organic ligand is a racemic salbinap and wherein the metal is selected from the group consisting of Y, Sc lanthanide elements, Group 14, transition elements, and Group 13 elements except thalium. In a preferred process, the lactide has the formula 
or the formula 
wherein R1 and R3 are selected from the group consisting of linear, branched, and unsaturated alkyl containing 1 to 24 carbon atoms and aryl, and hydrogen.
In one embodiment, the catalyst is rac-(salbinap)MOAlk wherein M is the metal and Alk is a lower alkyl containing 1 to 6 carbon atoms. In another embodiment, the catalyst is rac-(salbinap)AlEt wherein Et is ethyl. In an embodiment further still, the catalyst is rac-(salbinap)AlOiPr wherein iPr is isopropyl.
The present invention further provides a composition comprising a crystalline polylactic acid (PLA) prepared by the above process. In a preferred embodiment, the composition is rac-(salbinap)MOAlk wherein M is the metal and Alk is a lower alkyl containing 1 to 6 carbon atoms. In another embodiment, the composition is rac-(salbinap)AlOEt wherein Et is ethyl. In an embodiment further still, the composition is rac-(salbinap)AlOiPr wherein iPr is isopropyl.
Further, the present invention provides a process for the preparation of a polymandelide which comprises (a) providing anhydrous mandelide with a moisture content of less than about 2 mole % based on the mandelide; (b) mixing the mandelide with a metal organic ligand catalyst in an anhydrous solvent for the mandelide under anhydrous conditions to provide a reaction mixture; (c) heating the reaction mixture to polymerize the mandelide in the reaction mixture to form the polymandelide; and (d) separating the polymandelide from the reaction mixture. Preferably, the reaction mixture is heated to between about 60xc2x0 C. and 180xc2x0 C. to polymerize the mandelide and the mandelide is an R, S mandelide. For solutions the temperature for polymerization is preferably 70xc2x0 C. and for melt polymerization is preferably at xcx9c150-160xc2x0 C. In one embodiment, it is preferable that the solvent is removed from the reaction mixture in step (b) and then reaction mixture is heated in step (c) as a melt to polymerize the mandelide. In another embodiment, a solvent is introduced into the reaction mixture in step (b) along with an initiator for the reaction and then the reaction mixture is heated in step (c) to polymerize the mandelide.
The present invention further provides a polymandelide polymer produced according to the process of above. In particular, the present invention provides a polymandelide polymer having a molecular weight distribution of between about 12,000 and 100,000 preferably 50,000 and 100,000 and a Polymer Dispersity Index (PDI) of between 1.0 and 2.0.
Polydispersity Index (PDI) is Mw (weight average) divided by Mn (number average molecular weight). Mn is the average molecular weight per chain for a series of chains.
The term xe2x80x9cliving polymerizationxe2x80x9d means that the chain(s) grows, without being prematurely terminated, to a high molecular weight.
Therefore, it is an object of the present invention to provide a process and catalysts for the production of polymers from a racemic mixture of dimeric cyclic ester precursors.
Further, it is an object of the present invention to remove the requirement of first preparing enantiopure monomers before preparing the crystalline materials.
Further, it an object of the present invention to provide polylactide and polymandelide polymers and their derivatives and processes for the preparation thereof which is relatively simple and very economic.
A particular object of the present invention is to provide a racemic catalyst for preparing crystalline polylactide from a racemic mixture of D- and L-lactide.
The present invention also provides a process for preparing polymandelide from mandelide.